Modulating the function of G protein coupled receptors (GPCRs) is a common means by which the sensitivity of signaling pathways can be increased or decreased as circumstances dictate. Different accessory enhancing proteins can affect GPCR responsiveness in several ways: regulate expression, target subcellular localization, promote proper folding, or enhance association with G proteins. Olfactory receptors, rhodopsin and taste receptors are amongst the sensory GPCRs for which one or more accessory enhancing proteins have been found to modulate the receptor's response function - particularly important for receptors that must function to detect sensory stimuli over several orders of magnitude. Meyerhof and colleagues and we have found multiple RTPs (Receptor Transporting Proteins) and REEPs (Receptor Expression Enhancing Proteins) to be present in taste tissue. Contrary to the results of Meyerhof's group we observed that REEP2 is selectively expressed in taste cells and enhances the function of both sweet and bitter taste receptors. The experiments proposed here functionally characterize the roles of RTPs and REEPs, particularly REEP2, in promoting taste receptor function. In this proposal we combine molecular, cellular, transgenic, physiological and behavioral methods to determine: 1. which receptor enhancing proteins are expressed in which taste cells; 2. which receptor enhancing proteins interact with which taste receptors and by which sites; 3. how REEP2 and other REEPs/RTPs enhance sweet receptor function; 4. if REEP2 and and/or other REEPs/RTPs are involved in taste receptor function in vivo. This multidisciplinary approach has promise for providing significant new insights into the function and regulation of bitter, sweet and amino acid taste receptors within taste cells. This proposal has medical relevance to gustatory function, appetite, satiety, diabetes and obesity. PUBLIC HEALTH RELEVANCE: In many sensory systems accessory proteins regulate or enhance the function of the sensory receptor. We have found that one such receptor enhancing protein, REEP2, is selectively expressed in taste cells and enhances responses from bitter and sweet taste receptors but not from non-gustatory receptors. The experiments proposed to determine how REEP2 and other REEPs and RTPs interact with taste receptors and if this occurs in vivo have medical relevance to gustatory function, appetite, satiety, diabetes and obesity.